Most tissues exist in a highly regulated dynamic equilibrium wherein new tissue is formed and existing tissue is degraded and eliminated. The degradation of the extracellular matrix (ECM), including connective tissue and basement membranes, is effected by the metalloproteinases which are released from connective tissue and invading inflammatory cells. There are at least four distinct groups of the more than 20 matrix metalloproteinases (MMP) which have been identified (Birkedal-Hansen, H. J. Oral Pathol. 1988 17:445; Birkedal-Hansen, H. Curr. Opin. Cell Biol. 1995 7:728; Emonard, H.; Grimaud, J. A. Cell. Mol. Biol. 1990 36:131; Murphy, G.; Docherty, A. J. P. Am. J Respir. Cell Mol. Biol. 1992 7:120; Baramova, E.; Foidart, J. Cell Biol. Int. 1995 19:239; Borkakoti, N. Prog. Biophys. Mol. Biol. 1998 70:73; Johnson, L. L., Dyer, R., Hupe, D. J. Curr. Opin. Chem.Biol. 1998 2:466; Shapiro, S. D.; Senior, R. M. Am. J. Respir. Cell Mol. Biol. 1999 20:1100): the collagenases (interstitial collagenase, MMP-1; PMN collagenase, MMP-8, collagenase-3, MMP- 13), the gelatinases (gelatinase A, MMP-2, 72 kDa-gelatinase, Type IV collagenase; gelatinase B, MMP-9, 92 kDa-gelatinase, Type IV collagenase) the stromelysins (proteoglycanase, MMP-3, stromelysin-1, transin; stromelysin-2, MMP-10; stromelysin 3, MMP-11) and the membrane type matrix metalloproteinases (MT-1, MMP-14; MT-2, MMP-15; MT-3, MMP-16 and MT-4, MMP-17). Excessive unregulated activity of these enzymes can result in undesirable tissue destruction and their activity is regulated at the transcription level, by controlled activation of the latent proenzyme and, after translation, by intracellular specific inhibitory factors such as TIMP (xe2x80x9cTissue Inhibitors of MetalloProteinasexe2x80x9d) or by more general proteinase inhibitors such as xcex12-macroglobulins.
Inhibitors of MMPs also have been found to inhibit the release of the pleiotropic proinflammatory cytokine, tumor necrosis factor alpha which has be associated with the pathogenesis of numerous inflammatory, autoimmune, and neoplastic diseases. The protease, TNFxcex1-Converting Enzyme (TACE), catalyzes the release of TNFxcex1 from a membrane bound precursor protein.
The MMPs are a family of related proteolytic enzymes. They are zinc-binding metalloproteases linked by structural homology and by proteolytic activity against various components of the ECM while exhibiting divergent substrate specificity and activities. Calcium is generally required for maximum activity. They are distinguished from other metalloproteases by their susceptibility to activation of the zymogen by thiol-modifying reagents, mercurial compounds, N-ethylmaleimide and oxidized glutathione, by their inhibition by a group of endogenous substances known collectively as TIMPs, and by the presence of a consensus sequence in their propeptide forms. (H. Nagase, xe2x80x9cMatrix Metalloproteinases,xe2x80x9d chapter 7, ppl53-204 in Zinc Metalloproteases in Health and Disease xe2x80x9cN. M. Hooper (ed.), Taylor and Francis, London (1996)).
Many pathological conditions are associated with the rapid unregulated breakdown of extracellular matrix tissue by MMPs. Some of these conditions include rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration; periodontal disease, proteinuria, coronary thrombosis associated with atherosclerotic plaque rupture and bone disease. The process of tumor metastasis and angiogenesis also appears to be dependent on MMP activity. Since the cycle of tissue damage and response is associated with a worsening of the disease state, limiting MMP-induce tissue damage due to elevated levels of the proteinases with specific inhibitors of these proteases is a generally useful therapeutic approach to many of these debilitating diseases (for a general review see R C Wahl, et al. Ann. Rep, Med. Chem. 1990 25:175-184; Zask, A.; Levin, J. I.; Killar, L. M., Skotnicki, J. S. Curr. Pharm. Des. 1996, 2, 624).
It is an object of the present invention to provide novel selective, small molecule inhibitors of matrix metalloproteinases which can be used to modulate the progression of the underlying diseases and to treat diseases associated with excessive MMP-induced tissue damage.